Suicide is a major public health concern. Suicidal behavior occurs in the context of a diathesis that is characterized by traits in multiple domains: behavioral, clinical, personality, and biologic. While the complexity of suicidal behavior requires a multi-faceted prevention approach, the identification of neurobiological dysfunction is critical for the pharmacological interventions that may have protective effects against suicidal behavior. In this context, we have shown reduced BDNF gene expression and less activation of its cognate receptor TrkB in the brain of suicide subjects. In addition, we have found that p75NTR, a low affinity BDNF receptor is upregulated in the brain of these subjects. BDNF, which plays a critical role in neural plasticity and cell survival, essentially mediates its action via TrkB-mediated activation of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3 kinase (PI3K) signaling pathways. Abnormalities in these two signaling systems at the upstream levels were also found in the same brain areas of suicide subjects in which abnormalities were noted in BDNF/TRKB/p75NTR. These changes were present in all suicide subjects regardless of psychiatric diagnosis. To better understand the functional significance of altered BDNF signaling at molecular and cellular levels and their implications in the neurobiology of suicide, we propose to test the hypothesis that hypoactive BDNF/TrkB-mediated ERK1/2 and PI3K/Akt and overexpressed p75NTR will lead to modifications in the interaction and activation of downstream scaffolding/regulatory proteins, translational machinery, chromatin remodeling, and structural plasticity in the suicide brain. To test our hypothesis, in brain areas implicated in suicidal behavior, i.e., dlPFC and hippocampus (cerebellum as negative control brain region) from well-characterized and well-matched depressed suicide and non-psychiatric control subjects (n = 30 in each group), we aim to examine whether: 1) hypoactive ERK1/2 will lead to altered activation of substrates p90 ribosomal S6 kinase (RSK) and mitogen- and stress-activated kinase (MSK) and their mediated transactivation of transcription factors and chromatin remodeling; 2) hypoactive ERK1/2 and PI3K will lead to less active translational machinery, translation of postsynaptic genes, and altered dendritic morphology; and 3) altered PI3K/Akt and p75NTR will be associated with altered interactions of scaffolding proteins leading to c-Jun kinase (JNK) activation and altered expression and functional characteristics of downstream apoptotic regulatory proteins and neuronal apoptosis. To make sure that the effects are suicide specific, we will perform these studies in the same brain areas of an additional group of well-matched subjects who were depressed (no previous suicide attempt and no family history of suicide) and died by causes other than suicide (n = 30). Our proposed study will precisely and mechanistically assess the complexity of cellular signaling at the molecular, cellular, and functional levels in suicide brain and will have a significant impact in understanding not only the neurobiological basis of suicide but in designing more efficacious treatment strategies.